What is the treatment for carbapenem-resistant (CRO) Pseudomonas aeruginosa infections?

Treatment of Carbapenem-Resistant Pseudomonas aeruginosa Infections

For severe infections due to carbapenem-resistant Pseudomonas aeruginosa (CRPA), ceftolozane-tazobactam is the recommended first-line treatment if the organism is susceptible in vitro. 1, 2

Initial Treatment Approach

Severe Infections

• First-line therapy:
  • Ceftolozane-tazobactam 1.5g (1g/0.5g) IV q8h with appropriate renal adjustments if active in vitro 1, 2
  • Consider combination therapy with two in vitro active drugs when treating with polymyxins, aminoglycosides, or fosfomycin 1

Alternative Options (if ceftolozane-tazobactam is not available or not susceptible):

1. Ceftazidime-avibactam - Limited evidence for CRPA but may be effective 1, 3
2. Imipenem-relebactam 1.25g IV q6h 2
3. Cefiderocol - Consider for severe infections 1, 2
4. Colistin (polymyxin E) or Polymyxin B - 5 mg CBA/kg IV loading dose, followed by 2.5 mg CBA (1.5 CrCl + 30) IV q12h 1, 2, 4
   • Significant nephrotoxicity risk
   • Consider as part of combination therapy

Non-severe or Low-risk Infections

• Monotherapy with "old" antibiotics that are active in vitro based on susceptibility testing 1
• Select based on site of infection and individual patient factors 1

Treatment Considerations Based on Resistance Mechanisms

Metallo-β-lactamase (MBL) Producers

• MBLs (NDM, VIM, IMP) are common in CRPA and confer resistance to most β-lactams including ceftazidime-avibactam 5, 6
• For MBL-producing CRPA, consider:
  • Combination therapy with two in vitro active drugs 1
  • Polymyxins (colistin or polymyxin B) may be necessary 1, 4
  • Cefiderocol may retain activity against some MBL producers 2

Non-MBL Mechanisms

• For CRPA with non-carbapenemase mechanisms (efflux pumps, porin loss):
  • Ceftolozane-tazobactam often retains activity 1, 6
  • Anti-pseudomonal penicillins, cephalosporins, or fluoroquinolones may be effective if susceptible 1

Treatment Duration

• Complicated urinary tract infections: 5-10 days 2
• Complicated intra-abdominal infections: 5-10 days 2
• Ventilator-associated or hospital-acquired pneumonia: 10-14 days 2
• Bacteremia: 10-14 days 2

Important Clinical Pearls

1. Obtain infectious disease consultation - Strongly recommended for management of CRPA infections 1, 2

2. Antimicrobial susceptibility testing is essential - Results should guide definitive therapy 1, 2

3. Consider prolonged infusion of β-lactams for pathogens with high MICs 1, 2

   • Extended infusion improves pharmacodynamic target attainment

4. Avoid tigecycline monotherapy for CRPA infections - Lacks activity against P. aeruginosa 2

5. Monitor renal function closely when using polymyxins or aminoglycosides 2

6. Combination therapy considerations:

   • For severe infections treated with older agents (polymyxins, aminoglycosides)
   • No specific combination can be recommended over others 1
   • Base combinations on in vitro susceptibility testing 1

7. Antimicrobial stewardship - Restricting carbapenem use may help reduce CRPA rates in healthcare settings 7

Special Situations

Difficult-to-treat CRPA (DTR-PA)

• Defined as P. aeruginosa resistant to all standard antipseudomonal agents 1
• Consider newer agents (ceftolozane-tazobactam, ceftazidime-avibactam, imipenem-relebactam) if susceptible 1, 2
• For pan-resistant isolates, treatment with the least resistant antibiotic(s) based on MICs relative to breakpoints 1

Site-specific Considerations

• Pneumonia: Consider adjunctive inhaled therapy (colistin) for respiratory infections 1
• Bloodstream infections: Combination therapy may be beneficial 1
• Urinary tract infections: Aminoglycosides may be effective as monotherapy if susceptible 1